Project Summary Endothelial dysfunction is recognized as a key process in the development and progression of chronic kidney disease (CKD). Additionally, endothelial dysfunction is thought to contribute to the increased risk for CVD in this population. Impaired endothelial function is a primary event in the development of atherosclerosis and it is now recognized that cardiovascular disease (CVD) is the most important cause of morbidity and mortality in CKD. An understanding of the mechanisms responsible for endothelial dysfunction in CKD is important for improving renal and cardiovascular outcomes. Oxidative stress is elevated in patients with CKD and those on hemodialysis (HD) and has the potential to impair endothelial function. Thus, endothelial dysfunction secondary to oxidative stress may be a mechanism by which renal function deteriorates and CVD risk increases in CKD. Additionally, asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is elevated in CKD and can reduce NO production by competing with L-arginine for NOS. Thus, a relative deficit in L-arginine may result from the competition between ADMA and L-arginine for endothelial NOS. Investigations into the mechanism(s) of endothelial dysfunction in CKD have the potential to lead to development of therapeutic measures aimed at maintaining renal function and reducing cardiovascular risk. Most studies of endothelial function in renal disease have been performed in end stage renal disease and have focused on the macrocirculation. We propose to study endothelial function in patients with moderate to severe CKD before they require dialysis. Additionally, we propose to study the mechanisms of reduced NO bioactivity of the microcirculation by assessing cutaneous vasodilation in response to local heating by using laser Doppler flowmetry and intradermal microdialysis. Impaired microvascular function is a systemic process thus the skin provides an accessible site for the study of the microvasculature. The hyperemic response to local heating of the skin results in an initial peak that is axon-reflex mediated and a sustained plateau that is dependent on NO and provides a valuable tool for studying microvascular endothelial function. The aims of this study are 1) To determine if oxidative stress plays a mechanistic role in reducing nitric oxide-mediated cutaneous vasodilation in response to local heating in patients with moderate to severe CKD and 2) To determine if a relative deficit of L-arginine contributes to reduced nitric-oxide mediated cutaneous vasodilation in patients with moderate to severe CKD. These studies are innovative in that they will generate new information regarding the mechanisms of impaired NO bioactivity in the microcirculation of CKD patients. Therefore, the successful completion of this project would be expected to have a potentially important impact by expanding our understanding of endothelial dysfunction in CKD which may lead to therapies designed to maintain renal function and reduce cardiovascular risk in this population. Narrative The purpose of this project is to investigate the mechanisms of vascular dysfunction in chronic kidney disease in order to better understand the factors that lead to a progression of renal disease and the development of cardiovascular disease. Understanding these mechanisms may aid in the evaluation of therapies aimed at improving vascular function in chronic kidney disease.